SP #2: Imaging Markers of Early Pancreatic Cancer

Imaging Markers of Early Pancreatic Cancer

Significance:

Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer deaths in the United States, with a 5-year survival rate of only 5% and an average survival of less than 6 months [1]. Survival rates for PDA have remained unchanged for the past 30 years largely because clinical symptoms become evident only at a late stage of disease and methods for the early detection of this deadly disease are not available. The Bar-Sagi laboratory has been studying the role of oncogenic mutant forms of the Ras genes in cancer for more than two decades. Oncogenic mutations in the gene encoding K-Ras are nearly universal in human PDA and are believed to play a central role in the development of this malignancy [2,3].

Previous studies by Dr. Bar-Sagi and her group have exhibited a strong link between ubiquitination and endocytosis, which has led to an exploration of the relationship between macropinocytosis and Ras ubiquitination. They were able to show that oncogenic Ras proteins have the ability to stimulate macropinocytosis, a process by which extracellular fluid and its contents are internalized into the cell via membrane-bound vesicles known as macropinosomes [4].  Preliminary studies demonstrate that, in pancreatic cancer cells harboring oncogenic K-Ras, macropinocytosis is robustly activated and mediates the uptake of extracellular serum albumin.  Furthermore, this uptake activity can be detected at a pre-neoplastic stage of tumor development in an autochthonous mouse model of pancreatic cancer. These initial observations suggest that imaging approaches sensitive to enhanced albumin uptake could play a role in early diagnosis of pancreatic cancer. 

Recent work by the Bar-Sagi group, published in Nature since the original BTRC submission, has identified macropinocytosis as an important route of nutrient uptake in tumors, suggesting the possible exploitation of this process in the design of anticancer therapies [5].

Aims:

In this study, we will evaluate the feasibility of imaging early pancreatic cancer with albumin-associated MR and PET tracers.

Approach:

Our research plan will involve three principal components:

  1. We will evaluate suitable gadolinium-labeled and/or radioisotope-labeled albumin tracers in phantoms and in mice
  2. We will evaluate high-sensitivity, high-resolution abdominal image acquisition approaches suitable for robust pancreatic imaging in humans
  3. The BTRC radiofrequency engineering group will explore encircling coil arrays with high sensitivity for abdominal imaging.  They are also planning to develop a novel endoscopic coil array (Figure 1) taking ad­vantage of the proximity of the stomach and duodenum to the pancreas, to enable substantial further gains in signal-to-noise ratio.  Based on results of the previous investigation of albumin tracers, the SP team will esti­mate expected levels of albumin uptake and will work with BTRC staff to evaluate whether the performance of these coil arrays will suffice for early detection.

BTRC Resources Utilized:

TR&D #1: The novel volumetric imaging approaches developed in TR&D #3 should be well-suited for high-performance pancreatic imaging, and we will design human studies incorporating the new paradigm.

TR&D #2: Our prospective imaging biomarkers will have an impact only if they fall above the detection threshold for MR or PET imaging.  Unfortunately, the pancreas has proven to be a challenging organ for magnetic resonance imaging.  The coils to be developed take advantage of unique expertise of the BTRC.

TR&D #3: The pancreas is subject to abdominal motion, which will benefit from motion correction and other MR-PET reconstruction improvements. The combined MR-PET scanner will also afford the opportunity to explore multimodality tracers to improve sensitivity and specificity.

Principal Investigator: 

Sponsors

Latest Updates

10/31/2017 - 11:54
10/31/2017 - 11:37

Philanthropic Support

We gratefully acknowledge generous support for radiology research at NYU Langone Medical Center from:
 
• The Big George Foundation
• Raymond and Beverly Sackler
• Bernard and Irene Schwartz

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